title: Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients.
abstract: Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n=830), oxycodone (n=446), fentanyl (n=699), or other opioids (n=234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted opioid dose and were included as covariates. The patients were randomly divided into 1 development sample and 1 validation sample. None of 112 SNPs in the 25 candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed.
authors.affiliation: Pain and Palliation Research Group, Medical Faculty, Norwegian University of Science and Technology, Trondheim, Norway Department of Oncology, Oslo University Hospital, Oslo, Norway Rehabilitation and Palliative Care Unit, National Cancer Institute, Milan, Italy The Royal Marsden Hospital, Fulham Road, London, UK Kliniken Essen-Mitte, Essen, Germany Department of Palliative Medicine, Stockholms Sjukhem Foundation, Stockhalm, Sweden Department of Oncology Pathology, Karolinska Intitute, Stockhalm, Sweden Palliative Care Unit, Valerio Grassi Hospice, Forlimpopoli, Italy Department of Palliative Medicine, RWTH Aachen University, Aachen, Germany Comprehensive Pain Center, University Hospital "Carl Gustav Carus", Dresden, Germany Palliative Care Unit, National University Hospital of Iceland, Reykjavik, Iceland Oncological Palliative Medicine, Oncology, Department Internal Medicine and Palliative Care Center, Cantonal Hospital, St. Gallen, Switzerland Department of Public Health University of Aberdeen, Aberdeen, UK Department of Anaesthesiology and Emergency Medicine, St. Olavs University Hospital, Trondheim, Norway Department of Oncology, St. Olavs University Hospital, Trondheim, Norway.
authors.forename: P
authors.initials: P
authors.lastname: Klepstad
authors.forename: T
authors.initials: T
authors.lastname: Fladvad
authors.forename: F
authors.initials: F
authors.lastname: Skorpen
authors.forename: K
authors.initials: K
authors.lastname: Bjordal
authors.forename: A
authors.initials: A
authors.lastname: Caraceni
authors.forename: O
authors.initials: O
authors.lastname: Dale
authors.forename: A
authors.initials: A
authors.lastname: Davies
authors.forename: M
authors.initials: M
authors.lastname: Kloke
authors.forename: S
authors.initials: S
authors.lastname: Lundström
authors.forename: M
authors.initials: M
authors.lastname: Maltoni
authors.forename: L
authors.initials: L
authors.lastname: Radbruch
authors.forename: R
authors.initials: R
authors.lastname: Sabatowski
authors.forename: V
authors.initials: V
authors.lastname: Sigurdardottir
authors.forename: F
authors.initials: F
authors.lastname: Strasser
authors.forename: P M
authors.initials: PM
authors.lastname: Fayers
authors.forename: S
authors.initials: S
authors.lastname: Kaasa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000701:Analgesics, Opioid / Q000627:therapeutic use; D016009:Chi-Square Distribution; D005060:Europe / Q000453:epidemiology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications; D009293:Opioid-Related Disorders / Q000209:etiology / Q000235:genetics*; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D010147:Pain Measurement; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011957:Receptors, Opioid / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000701:Analgesics, Opioid; D011957:Receptors, Opioid